The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453000, China; Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, 16150, Malaysia.
Sanquan College of Xinxiang Medical University, XinXiang 453003, Henan, China.
Redox Biol. 2024 Nov;77:103376. doi: 10.1016/j.redox.2024.103376. Epub 2024 Oct 5.
The significance of protein S-palmitoylation in angiogenesis has been largely overlooked, leaving various aspects unexplored. Recent identification of Gpx1 as a palmitoylated protein has generated interest in exploring its potential involvement in novel pathological mechanisms related to angiogenesis. In this study, we demonstrate that Gpx1 undergoes palmitoylation at cysteine-76 and -113, with PPT1 playing a crucial role in modulating the depalmitoylation of Gpx1. Furthermore, we find that PPT1-regulated depalmitoylation negatively impacts Gpx1 protein stability. Interestingly, inhibiting Gpx1 palmitoylation, either through expression of a non-palmitoylated Gpx1 mutant or by expressing PPT1, significantly enhances neovascular angiogenesis. Conversely, in PPT1-deficient mice, angiogenesis is notably attenuated compared to wild-type mice in an Oxygen-Induced Retinopathy (OIR) model, which mimics pathological angiogenesis. Physiologically, under hypoxic conditions, Gpx1 palmitoylation levels are drastically reduced, suggesting that increasing Gpx1 palmitoylation may have beneficial effects. Indeed, enhancing Gpx1 palmitoylation by inhibiting PPT1 with DC661 effectively suppresses retinal angiogenesis in the OIR disease model. Overall, our findings highlight the pivotal role of protein palmitoylation in angiogenesis and propose a novel mechanism whereby the PPT1-Gpx1 axis modulates angiogenesis, thereby providing a potential therapeutic strategy for targeting PPT1 to combat angiogenesis.
蛋白质 S 棕榈酰化在血管生成中的意义在很大程度上被忽视了，导致许多方面尚未得到探索。最近发现 Gpx1 是一种棕榈酰化蛋白，这引起了人们对其在与血管生成相关的新病理机制中的潜在作用的兴趣。在这项研究中，我们证明 Gpx1 在半胱氨酸 76 和 113 处发生棕榈酰化，PPT1 在调节 Gpx1 的去棕榈酰化中起着关键作用。此外，我们发现 PPT1 调节的去棕榈酰化会对 Gpx1 蛋白稳定性产生负面影响。有趣的是，抑制 Gpx1 的棕榈酰化，无论是通过表达非棕榈酰化的 Gpx1 突变体还是表达 PPT1，都能显著增强新血管生成。相反，在 PPT1 缺陷型小鼠中，与野生型小鼠相比，在氧诱导的视网膜病变（OIR）模型中，血管生成明显减弱，该模型模拟了病理性血管生成。在生理条件下，缺氧条件下 Gpx1 的棕榈酰化水平急剧降低，表明增加 Gpx1 的棕榈酰化可能具有有益的效果。事实上，通过抑制 PPT1 用 DC661 增强 Gpx1 的棕榈酰化，可有效抑制 OIR 疾病模型中的视网膜血管生成。总之，我们的研究结果强调了蛋白质棕榈酰化在血管生成中的关键作用，并提出了一种新的机制，即 PPT1-Gpx1 轴调节血管生成，从而为靶向 PPT1 以对抗血管生成提供了一种潜在的治疗策略。
